Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates

Abstract

Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC-inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface

“…Large acyl loop backbone rearrangements have also been seen in mouse AChE and T. californica AChE inhibited by the OP pesticide diisopropyl fluorophosphate (DFP), but not in the hAChE:fasciculin‐II complex inhibited by tabun in the aged state, the only other reported structure of OP‐inhibited hAChE solved to date. A more recent structure of DFP‐inhibited mouse AChE (PDB code 5HCU) shows significantly less perturbation of the acyl loop; however, high atomic B‐factors of the adduct suggest improper modeling of full occupancies in a complex that is likely only partially formed. Differences in acyl loop conformations seen in hAChE and mouse AChE when inhibited by paraoxon and DFP likely results from differences in the van der Waals volumes of the formed adducts.…”

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

“…Non-oxime reactivators. [113,114] Chem.E ur.J. 2019 Review tiple formso fb oth OP pesticidea nd nerve-agent-inhibited AChE.…”

“…Pyridine-basedt herapeutics are effective,but their binding and efficacy are significantly increased when the therapeutics are alkylated to form the pyridinium.T he positivec hargei ncreases affinity for the active site throughc ation-p interactions with Trp86. [113] Recently,m ore and more nucleophilicc ompounds, which are non-oximes, have been studied in order to find structurale lements that provide similar binding affinitiesa nd rates of reactivation without the need to change the chargeo f the compound to facilitate binding and/orefficacy. Stojanovic et al took au nique approach of screening al ibrary of 2000 bioactive and approved drugs for their ability to reactivate OP-inhibited AChE.…”

“…Stojanovic et al took au nique approach of screening al ibrary of 2000 bioactive and approved drugs for their ability to reactivate OP-inhibited AChE. [113] The screenr esulted in two initial leads:t he antimalarial drug amodiaquine and scopoletin ( Figure 27). Amodiaquinew as chosen as the compound of initial focus as scopoletin was effective against paraoxon-inhibited AChE, but not DFP-inhibited AChE.…”

“…Unfortunately,n oneo ft he synthesized analogues outperformed 41.As imilar set of compounds to that of 41 was tested drawing from the structure of 42 which was reported in their originals tudy. [113] The new compounds replaced the imidazole moiety of 42 with apyridine moiety,and three analogues were synthesized with methylene linkersr angingf rom 1-3units. The newly synthesized compoundsd id show reactivation potential, but no increase in effectiveness, and the new compounds were all outperformed by 42.O ne of the reactivators (44, Figure 28) from the initial screen was noted for its features that were similart od onepezil and its reactivation potency was similart o41 and 42.A dditional donepezil-inspired analogues, such as 43,w eres ynthesized andp ossessede ither a piperidinyl or piperazinyl ring attached to the pyridyl ring.…”